This invention relates to a method and device for delivering drugs to the body through intact skin and more particularly to such devices which incorporate a pressure sensitive adhesive and even more particularly to such devices having at least two phases, a phase formed of a polymer matrix having limited water solubility and, in admixture, an interpenetrating phase of drug, polymer, liquid such as a solvent or a solid, or one or more of the foregoing.
Devices that deliver drugs through intact skin, namely the epidermis, for absorption into the body and the systemic circulatory system have been known for some time. Such devices can be referred to as transdermal drug delivery devices or dermal compositions.
The purpose of such devices is to dispense a drug at a controlled, and if desired, constant rate by presenting the drug in an efficient manner, with the minimum degradation or complications from the drug or from failure to comply with the therapeutic regimen.
A typical prior art system using a polymer matrix involves diffusion of the drug at a controlled rate through the polymer. However, such systems, as a result of the need for a rate limiting means, are more complicated to manufacture. For example, U.S. Pat. Nos. 3,948,262, 4,144,317 and 4,379,454 assigned to Alza and Ciba relate to transdermal drug delivery systems. The controlled delivery devices of those patents are structurally distinct, operate differently and accordingly, do not provide the delivery kinetics obtained with the system of this invention.
It is known to deliver drugs from natural or synthetic rubbers, or from acrylic polymers or from ethylene vinyl acetate, the drugs passing from the polymers by diffusion. It is also known from related application U.S. Pat. No. 4,814,168 to use a multipolymer adhesive incorporating a drug. It is further known from related application Ser. No. 295,847 filed Jan. 11, 1989, now U.S. Pat. No. 4,994,267 to use a combination of a rubber, acrylic and ethylene vinyl acetate polymers as the multipolymer.
It is known to use fillers in transdermal drug delivery devices U.S. Pat. No. 4,421,737 refers to fillers used traditionally for ordinary adhesive tapes in connection with a nitroglycerin transdermal drug delivery device. That patent further indicates that "kaolin and clay" are fillers with mild acidity which can be used to absorb nitroglycerin to regulate nitroglycerin release. The patent indicates that the use of the filler is optional, but that when the filler is used it can be used in amounts up to two times the amount by weight of the adhesive, with the drug nitroglycerin representing 1 to 10% by weight of the "whole amount of the adhesive." The preferred range of filler was indicated to be from about 0 to 1.2 times the weight of the adhesive, with the nitroglycerin representing 1 to 10% of "the whole amount of the adhesive." Thus in U.S. Pat. No. 4,421,737 the drug nitroglycerin was a minor component of the system. Since nitroglycerin acts as a plasticizer for the adhesive, increasing amounts lead to increasing tackiness and eventually liquidity. Thus the clay functions as an absorbent for the liquid nitroglycerin to decrease the liquifying effect of the nitroglycerin.
Of increasing interest are transdermal drug delivery devices in which the drug is incorporated into a pressure sensitive adhesive, which serves not only to carry the drug, but to attach the device to the skin.
The introduction of a drug into a pressure sensitive adhesive, as distinct from carrying the drug in a separate structure of the device, results in a variety of delivery and adhesion problems.
Adhesion problems vary with, among other things, the nature of the polymers forming the pressure sensitive adhesive, the type and amount of drug, the type and amount of other ingredients in the system and the conditions of use.
The transdermal device must be strong enough to adhere to the wearer for a specified length of time. Otherwise the individual will not receive the prescribed amount of medication However, if the adhesion is too strong, the wearer may encounter mechanical irritation upon removal. Adhesiveness of any device varies with time on the skin. Initial adhesion may be adequate However, when the wearer begins to perspire, adhesiveness may be reduced.
Various attempts have been made to overcome the delivery deficiency problems of the prior art transdermal systems. Gels formed of crosslinked hydrophilic polyacrylamide and polyvinylpyrrolidone polymers have been used as carriers However, the single phase gel compositions did not lead to systems having acceptable release properties because the duration of release depends upon the density of the gel, which property is difficult to control with standard manufacturing techniques. U.S. Pat. No. 4,391,797 attempted to solve such problems, particular for implants and drugs having a molecular weight of at least 1000 by combining a relatively water insoluble polymer matrix such as ethylene vinyl acetate copolymer with a swellable, hydrophylic drug having a molecular weight of at least 1000.
It is also known that the inclusion of a solid in an ethylene vinyl acetate polymer can result in pore formation. See Grace U.K. Patent Specification No. 1,126,849.
One aspect of this invention is based on the finding that it is not at all necessary or desirable to control the release of the drug from the polymer, for example, by a rate limiting membrane, so that there is a uniform delivery rate per unit time. Rather, improved results are obtained when the drug is delivered to the skin as rapidly as practicable, namely where the rate of release is not constant, but decreases over time. This more rapid release in fact may result in improved delivery of the drug to the body system as shown by blood levels of drug having a more narrow therapeutic range and smaller peak to trough ratios.
Another aspect of this invention is the finding that the addition of a clay to a transdermal drug delivery device, namely a dermal composition, increases the adhesiveness of such device. Specifically, one aspect of this invention is the addition of an adhesiveness increasing amount of a clay to a mixture of a drug and a pressure sensitive adhesive, particularly an adhesive containing a solvent for one or more of the components of the composition.
This invention also permits more rapid release of the drug while increasing adhesiveness.
The clay is used in an adhesiveness increasing amount, which in any event is a minor amount based on the total weight of the composition. The term "a minor amount" used here means less than about 50% and preferably less than 20% and more preferably less than about 10% or even about 5% by weight of the total composition. Use of higher amounts of clay results in an unacceptable retardation in the release rate of the drug. Surprisingly, it has been found that the addition of a clay increases the adhesiveness of a tacky polymer, despite previous reports that clay reduces cohesiveness and impliedly adhesiveness.